Desmosomes are cell junctions that connect epithelial cells. Defects in these junctions cause acquired and inherited diseases of the skin, its appendages and the heart. Cell culture experiments provided evidence that desmocollins (dsc), which are transmembrane components of desmosomes, are crucial for cell adhesion and the connection of desmosomes to the intermediate filament cytoskeleton of epithelial cells. This application focuses on dsc3, which we have shown to be required for normal embryonic development in the mouse. In vitro experiments suggest that dsc3 plays an important role in the development and differentiation of ectoderm-derived tissues and organs, most likely by providing selective adhesion between cells from the same differentiation pathway. Furthermore, evidence is accumulating that dsc3 might function as tumor suppressor in certain carcinomas. To define the role of dsc3 in vivo, we propose the following specific aims: 1. To elucidate the role of dsc3 in early embryonic development by analyzing dsc3 knockout mice that we have generated. 2. To determine the contributions of dsc3 to development and maintenance of the skin by ablating dsc3 expression in conditional dsc3 null mice at different time points during embryonic and postnatal development. We will employ a Cre/LoxP-based gene knockout system that allows systemic and focal gene ablation. 3. To characterize the effects of dsc3 ablation on desmosome assembly and function in-vitro by analyzing dsc3 null keratinocytes. 4. To determine whether dsc3 gene ablation facilitates tumor progression in mice subjected to a skin carcinogenesis protocol by inactivating the dsc3 gene at different stages of tumor conversion from benign papillomas to invasive carcinomas.